Citations

Abstract Background: Genomic testing is a cornerstone of precision oncology, yet certain communities remain underrepresented in its uptake. Limited genetic literacy, medical mistrust, and access barriers persist, particularly among populations at higher risk for prostate cancer. Community-driven approaches are urgently needed to promote equitable engagement in precision cancer care. Methods: To explore community perspectives and inform intervention development, a 31-member Community Advisory Board (CAB) was convened cross Duval County (FL), Maricopa County (AZ), and Olmsted County (MN). CAB members, representing racially, ethnically, and geographically diverse stakeholders, participated in small-group discussions (n=5) using a mixed-methods framework. Qualitative and quantitative data were collected to assess knowledge, perceptions, and barriers to genetic testing for prostate cancer. Results: Three overarching themes emerged: (1) limited awareness of the existence and purpose of genetic testing for prostate cancer; (2) the need for culturally tailored messages and trusted community messengers to raise awareness; and (3) persistent structural and informational barriers to accessing care. Participants emphasized the role of non-clinical, community-trusted individuals in delivering messages that resonate and build trust within their communities. Conclusions: Findings highlight the critical importance of community-engaged, culturally responsive strategies to advance genomic literacy and reduce disparities in prostate cancer care. This formative work will directly inform the design of a targeted, community-based educational intervention to improve equitable access to genomic testing among underserved populations. Funding: This work was supported by National Cancer Institute Grant 1K01CA23019301 Citation Format: Ewan K. Cobran, Jocelyn Turner, Laureen Husband. Advancing equitable access to prostate cancer genomic testing through community-informed and culturally tailored strategies [abstract]. In: Proceedings of the 18th AACR Conference on the Science of Cancer Health Disparities; 2025 Sep 18-21; Baltimore, MD. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2025;34(9 Suppl):Abstract nr B059.

Abstract Repetitive head impacts are associated with structural brain changes and an increased risk for chronic traumatic encephalopathy, a progressive neurodegenerative disease that can only be diagnosed after death. Chronic traumatic encephalopathy is defined by the abnormal accumulation of phosphorylated tau protein, particularly at the depths of the superior frontal sulci, suggesting that sulcal morphology may serve as a relevant structural biomarker. Contact sport athletes, such as former football players, are at elevated risk due to their prolonged exposure to repetitive head impacts. Cortical atrophy linked to underlying tau accumulation may result in shallower and wider sulci, potentially making sulcal morphology an imaging marker for identifying individuals at risk for this disease. This study investigated sulcal morphological differences in former football players and examined associations with age, football-related exposure, clinical diagnosis of traumatic encephalopathy syndrome, levels of certainty for chronic traumatic encephalopathy pathology, neuropsychological performance, and positron emission tomography imaging using flortaucipir. We analysed structural magnetic resonance imaging data from 169 male former football players (mean age 57.2 (8.2) years, range 45–74) and 54 age-matched, unexposed asymptomatic male controls (mean age 59.4 (8.5) years, range 45–74). Sulcal depth and width were quantified using the CalcSulc, focusing on two regions in each hemisphere commonly affected by chronic traumatic encephalopathy pathology: the superior frontal and occipitotemporal sulci. Generalized least squares models were used to assess group differences and interactions with age and football exposure variables, including age of first exposure, total years played, and cumulative head impact exposure. An analysis of covariance evaluated relationships between sulcal morphology, clinical measures, and flortaucipir uptake, adjusting for age, race, body mass index, education, imaging site, apolipoprotein E4 status, and total intracranial volume. Former football players demonstrated significantly shallower sulcal depth in the left superior frontal sulcus compared to unexposed controls. Earlier age of first exposure and longer football careers were associated with greater widening of the left occipitotemporal sulcus. Higher cumulative head impact exposure was linked to reduced sulcal depth in the left superior frontal region. However, sulcal morphology was not associated with clinical diagnosis, levels of certainty, neuropsychological test performance, or flortaucipir imaging. These findings suggest that sulcal morphology may reflect cumulative exposure to repetitive head impacts, particularly in brain regions vulnerable to chronic traumatic encephalopathy pathology. Future ante- and post-mortem validation studies are needed to determine whether sulcal morphology can serve as a reliable in vivo biomarker of risk.

BACKGROUND AND OBJECTIVES Recent changes in European diagnostic criteria allow for serologic diagnosis of celiac disease in children. Those guidelines have not been adopted in North America; hence, we aim to assess the positive predictive value (PPV) of tissue transglutaminase (tTG) immunoglobulin A (IgA) assays used in North America in identifying histologic findings of celiac disease. METHODS Multicenter retrospective cohort study of children (<18 years) with an elevated tTG IgA within 6 months of an esophagogastroduodenoscopy between January 2016 and December 2021. Biopsy-confirmed celiac disease was determined by the presence of intraepithelial lymphocytosis and villous atrophy. The primary outcomes were the PPV of an elevated tTG IgA and tTG IgA greater than or equal to 10 times the upper limit of normal (10× ULN). RESULTS Overall, 4019 children (63.3% female; 9% type 1 diabetes, 2% Down syndrome) were included. Histologic findings were consistent with celiac disease for 3321 children (PPV = 82.6% [95% CI, 81.4–83.8]). Among the 1739/4019 (43.2%) children with tTG IgA greater than or equal to 10× ULN, 1651 had biopsy-confirmed celiac disease (PPV10× = 94.9% [95% CI, 93.8–95.9]). Five percent (88/1739) of children did not have histologic findings of celiac disease, including 41/1739 (2%) with normal histology. Diagnostic accuracy of tTG IgA varied widely among assays used in North America (PPV range: 71.5%–88.8%; PPV10× range: 89.3%–97.3%). Assays performed worse in children with type 1 diabetes (PPV10× 89% [95% CI, 83.5–92.8]). CONCLUSIONS Elevated tTG IgA in isolation is insufficient to confidently diagnose celiac disease. As tTG assay performance varied widely, diagnostic confirmation by a specialist prior to dietary changes is essential.

Abstract The idea that it might be possible to prevent some forms of amyotrophic lateral sclerosis and frontotemporal dementia has finally come of age. The hexanucleotide repeat expansion in the C9orf72 gene accounts for ∼10% of all amyotrophic lateral sclerosis and 10%–15% of all frontotemporal dementia diagnoses, with the two clinical syndromes co-manifesting in a significant number of patients. As a result, clinically unaffected carriers of pathogenic C9orf72 repeat expansions are currently the largest identifiable population at significantly elevated risk for both amyotrophic lateral sclerosis and frontotemporal dementia, and in whom it might be possible to prevent the emergence of clinically manifest disease. Strategies for the design of disease prevention trials among clinically unaffected C9orf72 carriers have begun to emerge separately in the amyotrophic lateral sclerosis and frontotemporal dementia fields. However, recognition of the need to define neurodegenerative diseases based on biology underscores the need to consider all potential clinical manifestations of a C9orf72 repeat expansion together, rather than the traditional siloed approach of focusing on only amyotrophic lateral sclerosis or only frontotemporal dementia. Indeed, emerging clinical and biological markers that might be used to quantify pre-symptomatic disease progression and to predict the short-term risk of phenoconversion to clinically manifest disease are shared across the phenotypic spectrum. Given the anticipated progress in the development of therapeutic strategies to target the C9orf72 repeat expansion, and the enthusiasm for prevention trials among the unaffected C9orf72 repeat expansion carrier population, now is the time to begin work on the design of disease prevention trials. To this end, The Association for Frontotemporal Degeneration and The ALS Association supported a multi-stakeholder workshop (in Washington D.C., June 2024) to unify efforts to design a prevention trial for the population at elevated genetic risk for the phenotypic spectrum of C9orf72 disease. Here we describe recommendations emanating from this workshop for the selection of outcome measures, delineation of eligibility criteria, optimal use of biomarkers and digital health technologies, potential analytic frameworks and relevant regulatory considerations related to C9orf72 disease prevention trials. We also emphasize the importance of the amyotrophic lateral sclerosis and frontotemporal dementia communities working together in partnership with the C9orf72 repeat expansion carrier community, the regulatory authorities and the broader drug development community.

OBJECTIVE Coexisting medical conditions are increasingly prevalent in surgical populations. The impact of multiple comorbidities on patient-reported outcomes (PROs) and endotypes of frequently co-occurring conditions for cervical spondylotic myelopathy (CSM) remain unclear. This study explores whether CSM patients with multimorbidity have worse baseline and postoperative PROs and less functional improvement after surgery compared to those with few or no comorbidities. The authors also investigated whether distinct comorbidity endotypes exist among CSM surgical patients and whether they influence postoperative outcomes. METHODS The prospective Quality Outcomes Database (QOD) was used to assess patients undergoing surgery for CSM. Multimorbidity was defined as ≥ 2 chronic conditions, including diabetes, coronary artery disease, peripheral vascular disease, arthritis, chronic renal disease, chronic obstructive pulmonary disease, Parkinson’s disease, multiple sclerosis, depression, and anxiety. Baseline characteristics and 24-month PROs were assessed across multiple-comorbidity status, including modified Japanese Orthopaedic Association (mJOA), Neck Disability Index (NDI), visual analog scale for neck and arm pain, EQ-5D, and patient satisfaction scores. Clusters were identified from the full cohort using k-medoids, revealing subgroups with similar comorbidity endotypes. RESULTS The final cohort included 1141 CSM patients (83.1% reaching 24-month follow-up), with 761 (66.7%) having 0 or 1 comorbidity and 380 (33.3%) ≥ 2 comorbidities. The multimorbidity cohort was older (mean age 62.6 ± 11.2 vs 59.5 ± 12.0 years, p < 0.001), more likely to be female (52.9% vs 44.7%, p = 0.011), and had a higher BMI (mean 31.1 ± 6.7 vs 29.7 ± 6.2 kg/m 2 , p < 0.001). Multimorbidity patients exhibited worse mJOA, NDI, and EQ-5D scores at baseline and 24 months (p < 0.05). On multivariable analysis, the total number of comorbidities was not significantly associated with any PRO measures. Four comorbidity clusters were identified: low burden, arthritis, diabetes, and high burden. On one-way ANOVA, the baseline mJOA score was significantly different across clusters (p = 0.003). At 24 months, the mJOA score was significantly lower in the diabetes and high-burden endotypes. Twenty-four-month score change and minimal clinically important difference (MCID) achievement of all PROs remained similar across clusters (p > 0.05). CONCLUSIONS While patients with multimorbidity have worse baseline and postoperative PROs, they achieve similar functional and pain-related improvements following CSM surgery. Similarly, the comorbidity endotypes identified in this QOD cohort suggest that certain patterns of coexisting chronic conditions, such as overlapping diabetes and arthritis, are associated with different levels of disability but may not diminish the effectiveness of surgical intervention.

The translation of AI-generated brain metastases (BM) segmentation into clinical practice relies heavily on diverse, high-quality annotated medical imaging datasets. The BraTS-METS 2023 challenge has gained momentum for testing and benchmarking algorithms using rigorously annotated internationally compiled real-world datasets. This study presents the results of the segmentation challenge and characterizes the challenging cases that impacted the performance of the winning algorithms. Untreated brain metastases on standard anatomic MRI sequences (T1, T2, FLAIR, T1PG) from eight contributed international datasets were annotated in stepwise method: published UNET algorithms, student, neuroradiologist, final approver neuroradiologist. Segmentations were ranked based on lesion-wise Dice and Hausdorff distance (HD95) scores. False positives (FP) and false negatives (FN) were rigorously penalized, receiving a score of 0 for Dice and a fixed penalty of 374 for HD95. The mean scores for the teams were calculated. Eight datasets comprising 1303 studies were annotated, with 402 studies (3076 lesions) released on Synapse as publicly available datasets to challenge competitors. Additionally, 31 studies (139 lesions) were held out for validation, and 59 studies (218 lesions) were used for testing. Segmentation accuracy was measured as rank across subjects, with the winning team achieving a LesionWise mean score of 7.9. The Dice score for the winning team was 0.65 ± 0.25. Common errors among the leading teams included false negatives for small lesions and misregistration of masks in space. The Dice scores and lesion detection rates of all algorithms diminished with decreasing tumor size, particularly for tumors smaller than 100 mm3. In conclusion, algorithms for BM segmentation require further refinement to balance high sensitivity in lesion detection with the minimization of false positives and negatives. The BraTS-METS 2023 challenge successfully curated well- annotated, diverse datasets and identified common errors, facilitating the translation of BM segmentation across varied environments and providing the tools for future development of personalized volumetric reports to patients undergoing BM treatment.